Recent epidemiologic studies show that exposures to particulate air pollution, far below the current National Ambient Air Quality Standards, are associated with increased morbidity mortality in people with cardiopulmonary disease. This project focuses upon discovery of mechanisms by which inhaled ambient particles may produce such effects. Studies from our laboratories have shown: 1) inhalation of concentrated ambient particles (CAPs) results in as high as 37 percent mortality in animals with pre-existing pulmonary inflammation, but no mortality and no detectable effects on the lungs of normal anamils; 2) with exposure to environmental particles, suing our sensitive technology, significant cardiac electrophysiologic alterations are found even in normal animals; 3) CAPs initiate production of oxidants and cytokines in inflammation-primed lung cells comparable in magnitude to highly toxic alpha-quartz, and reactive oxygen species directly induce pro-inflammatory cytokines. Concepts basic to our approach are: 1) ambient air particles should be used for study; 2) the exposed populations should model affected human populations; and 3) the adverse effects should include increased mortality and morbidity observed in people. The central hypothesis is: Ambient air particles are complex mixtures with intrinsic toxicity. In concert with pre-existing inflammation, particulate exposure results in stimulation oflung receptors, release of reactive oxygen species, and pro-inflammatory mediators that lead to local and systemic effects, which ultimately account for the epidemiological associations. Our studies will utilize: 1) the Harvard Ambient Particulate Concentrator, a newly developed device that can increase ambient particle concentrations up to 30X without changing the physical or chemical characteristics of the particles; 2) an urban aerosol typical of the northestern US with ambient fine particle concentrations usually 5-15 gu/m3; 3) animal models of chronic bronchitist, coronary heart disease, and asthma to simulat affected human populations and to elucidate mechanistic effects; 4) established cell, molecular, and systems physiology methods to test mechanistic hypotheses; and 5) analytical capabilities to relate specific particulate constituents to adverse responses. The study consists of 3 projects and 3 cores: 1) Air Particles Cause Death in Animals with Lung Disease; 2) Cardiac Vulneraability due to Ambient Air Particle Exposure; 3) Responses of Inflammation-Primed Lung Cells to Particles; and Ambient Particle Exposure and Characterization Core. The novel application of these technique in coordinates studies will offer new insights into mechanisms of toxicity of ambient air particles.